The fish-hunting cone snails use their venoms to rapidly paralyze their much faster moving fish prey. These venoms contain multiple classes of paralytic toxins, as well as a large number of non-paralytic, but biologically active peptides. One of our major aims in the next grant period is to use these non-paralytic, biologically active peptides as a biochemical entry point for analyzing complex neurophysiological phenomena such as sleep. Our work can be divided into three groups of aims. First, we will investigate the omega-conotoxins, peptide toxins characterized by our laboratory in the last grant period, to study their target neuronal Ca channels. We will define different neuronal Ca channels subtypes, using different omega-conotoxins as probes. We will initiate purification of neuronal Ca channels using omega- conotoxin binding and crosslinking as assays. A second group of aims have to do with investigating the biologically active peptides which are not paralytic but exhibit biological activity when introduced into the CNS. Over 100 such peptides are apparently present in a single fish-hunting Conus venom. Two groups of these accessory peptides, those which induce highly specific behavioral syndromes (such as sleep, head shaking, etc.) and those which contain the modified amino acid tau-carboxyglutamate will be given highest priority for investigation. We have purified a tau-carboxyglutamate containing peptide which induces sleep in young mice, and a "climber" syndrome in older mice. Our objectives are to define the target of the sleeper/climber peptide, to explore development changes in the receptor target, and if feasible to purify these receptors. A third set of aims are a continuation of our work on the other paralytic toxins in fish-hunting cone venoms: these include investigation of a new class of paralytic toxins in the venom of Conus striatus, to continue ongoing studies on the mu-conotoxins and their interaction with muscle sodium channels, and to survey a number of additional fish-hunting cone venoms for novel, new paralytic toxins.